Ideas and Insight supporting all stages of Drug Discovery & Development

Hopes, Issues, and Concerns in Tackling the Challenge of Dementia

With recent failures of large Phase 3 studies targeting the amyloid pathways, there is perhaps a need for some good news for scientists, clinicians, health services and the general public. Recently, there was some good news in the media. Two elegant studies identified potential ways to rapidly access a novel therapy for dementia. The first aimed to identify small molecules capable of blocking prion-induced neurodegeneration. The authors took a functional screening approach with a focused set of small molecules and identified trazodone as effective in mitigating the neurodegenerative effects of prion protein (1). The second study hypothesized that umbilical cord plasma contains proteins capable of promoting neuroplasticity. They identified that TIMP2 (Tissue inhibitor of metalloproteinase 2) improved hippocampal function and mitigated age-induced memory impairments in mice (2). I was listening to a range of experts on different media sources describe how these important studies will help advance the cause of bringing new medicines to fight the terrible disease of dementia. They all mentioned the risks in medicine development and highlighted that trazodone has been in clinical use for many years and hoped appropriate clinical trials could be initiated to investigate the neuroprotective effects quickly.

I was struck by a sense of hope that there could be an approach that may make it to the marketplace quickly. I imagine that as we get older a greater sense of urgency in finding appropriate pharmacological interventions for dementia is a natural response. However, there did appear to be an “elephant in the room,” something that was not said but which everyone was probably aware of. Who would pay for the trials?

Trazadone is a generic drug. The risks and costs involved in bringing a new medicine into being are well known, and some level of commercial protection of your investment risk is a critical business factor. There are perhaps several issues that these studies raise that need resolution. Issues regarding intellectual property and pricing of drugs come to mind. Also, from an industry perspective, it is the potential commercial and scientific attractiveness that drive investments within a research portfolio. Attractiveness may be described in a range of measures (e.g. ease of development, scientific validation, peak year sales forecast), and it makes good business sense to focus on the best commercial return with the most likely candidates to be successful.

From a societal perspective, there is an issue of how to progress scientifically valid ideas that may not make the cut from a commercial perspective. If there were ways in which this could be achieved, another issue comes to mind: How would society choose which idea to progress? How many ideas would be progressed in parallel? How would society measure progress? There is no easy answer to these conundrums. These issues face industry as well, and the field of dementia is a hard one to engage with. For example, there seems no doubt that there is a pathological role for amyloid in the progression of Alzheimer’s disease, but we have still not been able to translate promising data in Phase 2 clinical trials to larger-scale studies so can we make effective therapies.

These issues raise a concern. Is the problem of tackling dementia just too big to be solved, especially in the near future? I hope not. However, some proactive approaches may need to be taken. With 25 years of research surrounding the amyloid hypothesis, there have been resounding failures in translating positive clinical signals to successful Phase 3 outcomes (3). We need to learn from past mistakes. We often think of the lack of positive data from failed clinical trials. However, if the trial was well conducted and managed, they have been successful even though they may not support the hypothesis that the agent is beneficial.

Allowing such clinical data to be reviewed and analyzed by the scientific community is one way to support the development of approaches. The problem is still one of understanding how to safely get the right medicine to the right person at the right time. Proactive discussion amongst societal and industrial stakeholders on how to incentivize and manage technical and investment risks effectively and develop different approaches to generating real world evidence will be important. If we don’t do something differently, there is a real risk that nothing will change.